The goals of this project is to investigate the metabolism of insulin and insulin-like growth factors. The project can be divided into three (3) major areas: 1. Studies of insulin metabolism: Previous studies on insulin degradation have relied on radioiodinated insulin. Since introduction of an iodine atom may alter the way insulin is metabolized, we have utilized rat islets to synthesize intrinsically labeled insulin from tritiated amino acids. We propose to study the metabolism of this tritiated insulin by perfused rat liver and rat hepatocytes. 2. Studies of insulin-like growth factors: Insulin-like growth factors (IGF) are peptides that are synthesized under the influence of growth hormone. IFG 1 is believed to be primarily responsible for somatic growth. The function of IGF 2 is not known. We have reasons to believe that IGF 2 may be involved in the regulation of growth hormone secretion. We have observed that insulin and IFG 2 both are degraded by insulin protease and will test the hypothesis that insulin degradation in vivo and in vitro is affected by IGF 1 and IGF 2. Finally we shall test the hypothesis that IFG 1 and 2 exert an anabolic effect in liver by inhibiting protein breakdown. 3. Serum factors that anatogonize insulin action: We have extracted a factor from the serum of an insulin resistant patient that inhibits insulin-stimulated glucose uptake by fat cells in vitro but increases 125I-insulin binding. We shall investigate the mechanism of action and structure of this substance, and determine if it is found in sera from other patients.